Di-substituted pyridinyl aminohydantoins as potent and highly selective human β-secretase (BACE1) inhibitors

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• 作者：Michael S. Malamas ; Keith Barnes ; Matthew Johnson ; Yu Hui ; Ping Zhou ; Jim Turner ; Yun Hu ; Erik Wagner ; Kristi Fan ; Rajiv Chopra ; Andrea Oll ; Jonathan Bard ; Menelas Pangalos ; Peter Reinhart ; Albert J.
• 关键词：Alzheimer’ ; s disease (AD) ; BACE1 inhibitors ; β ; -Amyloid peptide (Aβ ; ) ; Aminohydantoins
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2010
• 出版时间：15 January 2010
• 年：2010
• 卷：18
• 期：2
• 页码：630-639
• 全文大小：576 K

文摘

The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as β-secretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cell-based (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500×) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin.

Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2′ pocket (BACE1 Pro₇₀ changed to BACE2 Lys₈₆) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand’s affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC₅₀ value for BACE1 of 10 nM, and exhibited cellular activity with an EC₅₀ value of 130 nM in the ELISA assay.